Generation of tumor-reactive T cells from iPS cell-derived NKT cells and application for pancreatic cancer therapy

• Project/Area Number: 17K10717
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Digestive surgery
• Research Institution: National Cancer Center Japan
• Principal Investigator: Uemura Yasushi 国立研究開発法人国立がん研究センター, 先端医療開発センター, ユニット長 (40364781)
• Co-Investigator(Kenkyū-buntansha): 福田 恭子 (張エイ) 国立研究開発法人国立がん研究センター, 先端医療開発センター, 研究員 (00643719)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 外科 / がん / 免疫 / 再生医療 / 人工多能性幹細胞 / がん免疫療法 / NKT細胞 / キメラ抗原受容体 / iNKT細胞

Outline of Final Research Achievements

The re-iNKT cells by themselves showed the NK cell-like cytotoxicity against all of the tested cancer cell lines, which was mediated by NKG2D and DNAM-1. They inhibited the growth of K562 chronic myelogenous leukemia in a xenografted mouse model and prolonged the mouse survival. We generated the re-iNKT cells expressing a glypican-3 (GPC3)-reactive chimeric antigen receptor (CAR). The GPC3-CAR-transduced re-iNKT cells revealed a cytotoxicity against a GPC3-expressing SK-Hep1 cancer cell line. However, the strength of the cytotoxicity was equal to that of wild-type re-iNKT cells. To clarify the function of GPC3-CAR, we used peripheral blood-derived T cells for GPC3-CAR gene transfer. The GPC3-CAR-transduced T cells revealed the enhanced cytotoxicity against the GPC3-expressing JHH7 cell line compared to the wild-type T cells, indicating that the CAR construct is intact. re-iNKT cells can be a cell platform potentially utilized for cancer immunotherapy.

Academic Significance and Societal Importance of the Research Achievements

iNKT細胞は、アロ拒絶反応を惹起しないT細胞受容体を持つ為、iPSCから再生したiNKT細胞は、がん治療を目的とした他家投与用のエフェクター細胞プラットフォームとして有望である。再生iNKT細胞が抗腫瘍効果を示す「がん細胞」の情報は、学術的、及び 臨床的に重要である。

Research Products

• [Journal Article] Type I Interferon Delivery by iPSC-Derived Myeloid Cells Elicits Antitumor Immunity via XCR1+ Dendritic Cells. (2019)
  • Author(s): Tsuchiya N, Zhang R, Iwama T, Ueda N, Liu T, Tatsumi M, Sasaki Y, Shimoda R, Osako Y, Sawada Y, Kubo Y, Miyashita A, Fukushima S, Cheng Z, Nakaki R, Takubo K, Okada S, Kaneko S, Ihn H, Kaisho T, Nishimura Y, Senju S, Endo I, Nakatsura T, Uemura Y.
  • Journal Title: Cell Rep. Volume: 29 Issue: 1 Pages: 162-175
  • DOI: 10.1016/j.celrep.2019.08.086
  • Peer Reviewed / Open Access
• [Journal Article] In Vitro Detection of Cellular Adjuvant Properties of Human Invariant Natural Killer T Cells (2019)
  • Author(s): Zhang Rong、Kitayama Shuichi、Liu Tianyi、Ueda Norihiro、Tokumitsu Yumi、Mashima Hiroaki、Ohdan Hideki、Kaneko Shin、Uemura Yasushi
  • Journal Title: Methods Mol Biol Volume: 2048 Pages: 121-130
  • DOI: 10.1007/978-1-4939-9728-2_13
  • ISBN: 9781493997275, 9781493997282
  • Peer Reviewed / Open Access
• [Journal Article] Enhancing T cell Receptor Stability in Rejuvenated iPSC-derived T cells improves their use in cancer immunotherapy (2018)
  • Author(s): Minagawa A, Yoshikawa T, Yasukawa M, Hotta A, Kunitomo M, Iriguchi S, Takiguchi M, Kassai Y, Imai E, Yasui Y, Kawai Y, Zhang R, Uemura Y, Miyoshi H, Nakanishi M, Watanabe A, Hayashi A, Kawana K, Fujii T, Nakatsura T, Kaneko S
  • Journal Title: Cell Stem Cell Volume: 23 Issue: 6 Pages: 850-858
  • DOI: 10.1016/j.stem.2018.10.005
  • Peer Reviewed / Open Access
• [Journal Article] Generation of TCR-Expressing Innate Lymphoid-like Helper Cells that Induce Cytotoxic T Cell-Mediated Anti-leukemic Cell Response. (2018)
  • Author(s): Ueda N, Uemura Y, Zhang R, Kitayama S, Iriguchi S, Kawai Y, Yasui Y, Tatsumi M, Ueda T, Liu TY, Mizoro Y, Okada C, Watanabe A, Nakanishi M, Senju S, Nishimura Y, Kuzushima K, Kiyoi H, Naoe T, Kaneko S
  • Journal Title: Stem Cell Reports Volume: 10 Issue: 6 Pages: 1935-1946
  • DOI: 10.1016/j.stemcr.2018.04.025
  • NAID: 120006473765
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Co-delivery of tumor-derived exosomes with alpha-galactosylceramide on dendritic cell-based immunotherapy for glioblastoma (2017)
  • Author(s): Liu H, Chen L, Liu J, Meng H, Zhang R, Ma L, Wu L, Yu S, Shi F, Li Y, Zhang L, Wang L, Feng S, Zhang Q, Peng Y, Wu Q, Liu C, Chang X, Yang L, Uemura Y, Yu X, Liu T.
  • Journal Title: Cancer Lett. Volume: 411 Pages: 182-190
  • DOI: 10.1016/j.canlet.2017.09.022
  • Peer Reviewed / Int'l Joint Research
• [Presentation] iPSCに由来するプロフェッショナル抗原提示細胞を用いた新規がんワクチン療法の開発 (2019)
  • Author(s): 真島宏聡, 張エイ, 小林剛 岩間達章, 大段秀樹, 中面哲也, 植村靖史
  • Organizer: 第40回癌免疫外科研究会
• [Presentation] 人工多能性幹細胞に由来するプロフェッショナル抗原提示細胞を用いた新規がんワクチン療法の開発 (2019)
  • Author(s): 真島宏聡, 張エイ, 小林剛, 岩間達章, 大段秀樹, 中面哲也, 植村靖史
  • Organizer: 第23回日本がん免疫学会総会
• [Presentation] Type I interferon-delivery by iPSC-derived myeloid cells elicits antitumor immunity via XCR1+ dendritic cells (2019)
  • Author(s): Zhang R, Tsuchiya N, Liu T, Kubo Y, Miyashita A, Fukushima S, Ihn H, Senju S, Endo I, Nakatsura T, Uemura Y.
  • Organizer: 第78回日本癌学会学術総会
• [Presentation] Generation of proliferating professional antigen-presenting cells from induced pluripotent stem cells for cancer immunotherapy (2019)
  • Author(s): Mashima H, Zhang R, Kobayashi T, Liu T, Iwama T, Ohdan H, Nakatsura T, Uemura Y.
  • Organizer: 第78回日本癌学会学術総会
• [Presentation] Type I interferon-delivery by iPSC-derived myeloid cells elicits antitumor immunity via XCR1+ dendritic cells. (2019)
  • Author(s): Fukuda K, Tsuchiya N, Liu T, Kubo Y, Miyashita A, Fukushima S, Ihn H, Senju S, Endo I, Nakatsura T, Uemura Y
  • Organizer: 17th International Congress of Immunology, Beijing China
  • Int'l Joint Research
• [Presentation] 人工多能性幹細胞に由来する1型IFN産生ミエロイド細胞を用いたがん免疫療法 (2018)
  • Author(s): 張 エイ, 土屋 伸広, 得光 友美, 千住 覚, 遠藤 格, 中面 哲也, 植村 靖史
  • Organizer: 癌免疫外科研究会
• [Presentation] Type 1 IFN-delivery by myeloid cells from induced pluripotent stem cells elicits systemic antitumor immunity via dendritic cells (2018)
  • Author(s): Rong Zhang, Nobuhiro Tsuchiya, Tianyi Liu, Yosuke Kubo, Satoshi Nakahara, Azusa Miyashita, Satoshi Fukushima, Hironobu Ihn, Satoru Senju, Itaru Endo, Tetsuya Nakatsura, Yasushi Uemura
  • Organizer: 日本免疫学会
• [Presentation] Cellular adjuvant properties and direct cytotoxicity in re-differentiated Vα24 invariant NKT cells from human induced pluripotent stem cells (2017)
  • Author(s): Rong Zhang, Syuichi Kitayama, Tianyi Liu, Tatsuaki Iwama, Tetsuya Nakatsura, Shin Kaneko, Yasushi Uemura
  • Organizer: 第36回 札幌国際がんシンポジウム
  • Int'l Joint Research
• [Presentation] Induction of CD8 T cell-mediated anti-tumor immunity by type 1 IFN-producing myeloid cell therapy (2017)
  • Author(s): Tatsuaki Iwama, Nobuhiro Tsuchiya, Rong Zhang, Tianyi Liu, Miwa Haruta, Yosuke Kubo, Azusa Miyashita, Satoshi Fukushima, Hironobu Ihn, Yasuharu Nishimura, Satoru Senju, Itaru Endo, Tetsuya Nakatsura, Yasushi Uemura
  • Organizer: 第36回 札幌国際がんシンポジウム
• [Presentation] IFNα産生ミエロイド細胞を用いたがん免疫療法 (2017)
  • Author(s): 岩間 達章、土屋 伸広、張 エイ、得光 友美、春田 美和、劉 天懿、吉川 聡明、澤田 雄、久保 陽介、宮下 梓、福島 聡、田久保 圭誉、阪上-沢野 朝子、宮脇 敦史、尹 浩信、西村 泰治、千住 覚、遠藤 格、中面 哲也、植村 靖史
  • Organizer: 第21回 日本がん免疫学会総会
• [Presentation] Induction of T cell-mediated anti-tumor immunity by type 1 IFN-producing myeloid cells (2017)
  • Author(s): IWAMA Tatsuaki, TSUCHIYA Nobuhiro, ZHANG Rong, LIU Tianyi, KUBO Yosuke, MIYASHITA Azusa, FUKUSHIMA Satoshi, IHN Hironobu, ENDO Itaru, SENJU Satoru, NAKATSURA Tetsuya, UEMURA Yasushi
  • Organizer: 第76回 日本癌学会学術総会
• [Presentation] 1型IFNを産生するiPS細胞由来ミエロイド細胞を用いたがん免疫療法 (2017)
  • Author(s): 張 エイ, 得光 友美, 土屋 伸広, 岩間 達章, 下村 真奈美, 澤田 雄, 遠藤 格,中面 哲也, 千住 覚, 植村 靖史
  • Organizer: 第46回 日本免疫学会学術集会